This is an application for a K23 award for Dr. Rajat Deo, who proposes the use of rigorous epidemiologic and biostatistical methods to understand the role of the renin-angiotensin-aldosterone system (RAAS) in cardiac arrhythmias among people with chronic kidney disease (CKD). This award will allow Dr. Deo the resources and protected time to achieve the following career development goals: (1) to become an independent, clinical researcher in the field of cardiorenal disease and arrhythmias; (2) to become an expert in the application of causal inference methodology and sub-clinical measures of disease; and (3) to develop expertise in the methods critical to the adjudication process and rigorous design of cohort studies. To achieve these goals, Dr. Deo has assembled a mentoring team comprised of his sponsor and primary mentor, Dr. Harold Feldman (Principal Investigator and Chair of the Steering Committee for the Chronic Renal Insufficiency Cohort [CRIC]), and two co-mentors, Dr. Michael Shlipak (an expert in the field of cardiovascular complications of kidney disease) and Dr. Marshall Joffe (a senior biostatistician). Recent data demonstrate that CKD is associated with an increased risk of atrial and ventricular arrhythmias; however, the mechanisms underlying this predisposition remain unknown. Activation of the RAAS may mediate the risk of arrhythmias in patients with CKD. RAAS activation can affect cardiac conduction through both structural remodeling processes and direct ion channel inhibition. These structural and electrophysiological changes may be the precursors to atrial and ventricular arrhythmias. No study has evaluated the role of aldosterone as a mediator of arrhythmia risk in CKD. Using data from the CRIC study, Dr. Deo will evaluate baseline aldosterone with kidney function, electrocardiographic intervals and markers of conduction system disease, and arrhythmia outcomes. Three specific aims are proposed: Aim 1: To evaluate the association of kidney function with aldosterone concentrations in the CRIC study; Aim 2: To determine the cross-sectional and longitudinal associations of circulating aldosterone levels and kidney function with electrophysiological parameters of conduction system remodeling; and Aim 3: To determine the longitudinal associations of elevated aldosterone levels and reduced kidney function with atrial fibrillation and sudden cardiac death in CRIC. PUBLIC HEALTH RELEVANCE: Atrial fibrillation and sudden cardiac death risks are increased in patients with CKD, a highly prevalent disease in the United States. An improved understanding of the mechanisms implicated in these conditions could lead to important interventions and therapies to prevent the catastrophic complications of arrhythmias.